RESUMEN
Our understanding of dose-related effects of polymeric black tea polyphenols (PBPs), the most abundant polyphenols in black tea, is limited. In the present study, the effect of various doses of black tea (0.75, 1.5, and 3%)-derived PBP-rich extract on biochemical parameters and lung carcinogenicity in A/J mice was investigated. Pretreatment with PBPs showed the dose-related decrease in B(a)P-induced expression and activity of CYP1A1 in the liver while CYP1A2 expression and activity in the lung. Dose-dependent significant increase in PBP-mediated over-expression and activity of GSTs (alpha in the liver while pi in the lung) were observed in polyphenol-treated groups. Significant dose-related decrease in number and intensity of BPDE-DNA adducts were observed in liver and lung. Black tea (1.5%, 3%)-derived PBPs showed dose-mediated decrease in lung tumor incidence and multiplicity which was further correlated with different molecular markers like cell proliferation and apoptosis in B(a)P and NNK model. In conclusion, dose-dependent chemopreventive effects of PBPs, both anti-initiating (induction of phase II and inhibition of carcinogen-induced phase-I enzymes leading to decrease in BPDE-DNA adducts) and anti-promoting (decreased cell proliferation and increased apoptosis lowering incidence and/or multiplicity of lung lesions), were observed in A/J mice without significant toxicity.
Asunto(s)
Benzo(a)pireno/farmacología , Carcinogénesis/efectos de los fármacos , Neoplasias Pulmonares/prevención & control , Nitrosaminas/farmacología , Polifenoles/administración & dosificación , Té/química , Animales , Anticarcinógenos/administración & dosificación , Camellia sinensis/química , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP1A2/administración & dosificación , Aductos de ADN/análisis , Relación Dosis-Respuesta a Droga , Glutatión Transferasa/efectos de los fármacos , Hígado/enzimología , Pulmón/enzimología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Ratones , Extractos Vegetales/administración & dosificaciónRESUMEN
The aim of our study was to evaluate chemopreventive efficacy and possible mechanism of most abundant polyphenolic fraction in black tea, polymeric black tea polyphenols (PBPs), in experimental lung carcinogenesis model. Effect of 1.5% black tea derived PBPs on benzo(a)pyrene [B(a)P] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lung lesions were studied over 28 wks. Chemopreventive efficacy was studied using decrease in tumor incidence and/or multiplicity and/or delay in the latency period in A/J mice. Histopathological analysis of lung was carried out post-carcinogen treatment weeks to analyze the microscopic lung lesions. Inflammation, cell proliferation, and apoptosis markers along with signaling kinases like p38, Akt, and their phosphorylated forms were studied using immunoblotting and immunohistochemistry at 4th, 10th, and 18th wk post-carcinogen treatment. Administration of PBPs throughout the treatment period significantly decreased the multiplicity of surface tumors as well as microscopic lung lesions, including adenomas. Although tumor incidence and latency period remains unaffected, histopathological evaluation of lung at 6, 10, and 18 wks post- carcinogen treatment period showed decrease in tumor multiplicity which was also correlated with different molecular markers. Anti- inflammatory action of PBPs was demonstrated by reduced Cox-2 expression. PBPs down-regulated the B(a)P and NNK-induced cell proliferation (diminished PCNA expression, proliferation index, and Bcl-2 expression) and enhanced apoptosis (increased Bax expression and apoptotic index) potentially through phosphorylation of p38 and Akt. PBPs, most abundant polyphenolic component in the black tea, have chemopreventive effect through inhibition of inflammation, cellular proliferation, and induction of apoptosis possibly via modulation of signaling kinases. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/prevención & control , Pulmón/efectos de los fármacos , Polifenoles/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Té/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Anticarcinógenos/química , Apoptosis/efectos de los fármacos , Benzo(a)pireno , Carcinogénesis , Carcinógenos , Proliferación Celular/efectos de los fármacos , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Nitrosaminas , Fosforilación/efectos de los fármacos , Polifenoles/químicaRESUMEN
Success of imatinib in chronic myeloid leukemia (CML) therapy has undoubtedly proved utility of signalling molecules as therapeutic targets. However, development of imatinib resistance and progression to blastic crisis are the current challenges in clinics. To develop therapeutic alternatives for CML, understanding of signalling events downstream of bcr-abl might be helpful. Current CML cell lines do not give comprehensive picture of signalling events involved in pathogenesis of CML. Hence, there is a major unmet need for a better preclinical model for CML. Here, we report on development of RIN9815/bcr-abl, a novel cell line model that mimics signalling events in CML PMNL. Studies on crucial signalling molecules i.e., ras, rac, rhoA and actin in this cell line identified rhoA as the key regulator involved in CML cell function as well as proliferation of both, imatinib sensitive and resistant cells. Hence, RIN9815/bcr-abl could serve as the unique preclinical model in understanding pathogenesis of CML and in drug development.